Role of peroxisome proliferator-activated receptor α in atherosclerosis

Atherosclerosis is an inflammatory disease involving the immune response. In addition to lowering the cholesterol level, the peroxisome proliferator-activated receptor alpha (PPAR-alpha) can prevent atherosclerosis via its pleiotropic anti-inflammatory effects. However, the role of PPAR-alpha in modulating inflammatory progression of atherosclerosis has rarely been studied. Thus, we aimed to investigate the role of PPAR-alpha in atherosclerosis by evaluating the expression of inflammatory cytokines induced by PPAR-alpha in an in vivo rabbit model. New Zealand White rabbits were randomly divided into 5 groups: control, high-fat diet + balloon injury, high-fat diet + balloon injury + placebo, high-fat diet + balloon injury + fenofibrate, and high-fat diet + balloon injury + WY-14643. The femoral arteries of rabbits were balloon-injured after initiation of the high-fat diet and before administration of fenofibrate, WY-14643 or placebo solution. Atherosclerosis was induced by high-fat diet and balloon angioplasty, and the vessel wall lumen occlusion was determined by measuring the stenosis rate. PPAR-alpha gene expression was examined by quantitative polymerase chain reaction analysis. The cellular localization and distribution of PPAR-alpha was observed by immunohistochemistry, and its protein level was assessed by western blot analysis. The production of interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and P-selectin, which are major inflammatory factors involved in atherosclerosis, was monitored by an enzyme-linked immunosorbent assay (ELISA). Treatment with PPAR-alpha agonists (fenofibrate or WY-14643) reduced the vascular occlusion rate, as compared to the high-fat diet + balloon injury and the placebo groups. Furthermore, the expression of PPAR-alpha at both the protein and the mRNA level was increased in the fenofibrate and WY-14643 groups. According to the results, the TNF-alpha and P-selectin levels were reduced in the fenofibrate and WY-14643 groups. These results suggest that PPAR-alpha activation can attenuate the effects of atherosclerosis by inhibiting the expression of major inflammatory factors in a rabbit atherosclerosis model.